The present invention relates to a series of new biphenyl derivatives which have the ability to inhibit the action of angiotensin II (hereinafter abbreviated as AII) and which thus can be used for the treatment and prophylaxis of hypertension and cardiac diseases. The invention also provides methods and compositions using these new compounds as well as processes for their preparation.
It is known that the renin-angiotensin system provides one of the important mechanisms for maintaining the homeostasis of blood pressure in living animals. When blood pressure is reduced or the sodium ion concentration of the body fluids falls, this system is activated. As a result, the enzyme renin and angiotensin converting enzyme (hereinafter abbreviated, as is conventional, as "ACE") are activated and act on angiotensinogen, which is first decomposed by the renin to produce angiotensin I (hereinafter abbreviated as "AI"). This AI is then converted by ACE to AII. Since AII induces strong contractions of blood vessels and accelerates the secretion of aldosterone (a hormone which facilitates the storage of body fluids and sodium ions), the activation of the system results in an elevation of blood pressure. Inhibitors or suppressors of the renin-angiotension system, such as renin inhibitors, ACE inhibitors and AII antagonists, dilate blood vessels, cause reduced blood pressure and improve the circulatory function, which is the basis for the use of these agents in the treatment of heart diseases.
At present only ACE inhibitors are used clinically, although renin inhibitors and AII antagonists are under extensive investigation for such use. Of these, some peptide type AII antagonists, such as Saralasin, have been known for many years, whilst certain non-peptide type antagonists have recently been discovered (for example, as disclosed in European Patent Publications No. 28 833, 28 834, 245 637, 253 310 and 323 841 and in Japanese Patent Application Kokai No. Sho 57-98270 and Hei 3-63264). Most of the AII antagonists which have been found to have a comparatively strong activity have a (2'-carboxybiphenyl-4-yl)methyl group or a [2'-(tetrazol-5-yl)biphenyl-4-yl)methyl group in their molecule, for example, as disclosed in European Patent Publications No. 253 310 and 324 377, and in Japanese Patent Applications Kokai No. Hei 3-58942, Hei 3-63264 and Hei 3-95181.
The closest prior art, however, is believed to be European Patent Publication No. 545 912, assigned to the present assignees, which describes a series of 1-biphenylmethylimidazole derivatives having excellent AII antagonist activity, but which differ from the compounds of the present invention in several respects, principally in the nature of the substituents on the benzene ring of the biphenyl moiety which is not attached to the methylimidazole group.
However, the activities of these prior art compounds are still insufficient, and thus an AII antagonist having a stronger activity is desired for therapeutic use.
We have now discovered a limited series of biphenylmethyl derivatives having an excellent AII receptor antagonist activity, and which are therefore useful as anti-hypertensive drugs and for the therapy and prophylaxis of heart diseases.